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Medical Statistics and Informatics

Research Focus
General Facts
Research
Selected Publications
Selected Funding, Collaboration

Keywords: Medical Statistics, Biostatistics, Statistical Methods, Epidemiology, Medical Informatics, Medical Documentation, Clinical Trials, Registries, Risk Prediction, Causal Inference
Research (ÖSTAT Classification) : 305907, 305905, 305904, 303026, 303025

Research Focus

In cardiovascular and cancer epidemiology, we investigate metabolic and lifestyle factors as potential risk factors for disease incidence and mortality, with a special focus on the application of statistical mediation analyses within the framework of causal inference.

To establish a state-of-the-art biobanking infrastructure at MUI, a new deep learning model in medical imaging is being investigated and evaluated with respect to fundamental security vulnerabilities.

General Facts

The Institute of Medical Statistics and Informatics, formerly known as the Institute of Biostatistics and Documentation, was founded in 1969. We celebrated our 50th anniversary in 2019 (Fig. 1).


Fig. 1: 50th Anniversary of Biostatistics in Innsbruck

We organised a seminar with Ben Van Calster from KU Leuven as the keynote speaker, welcoming many partners and friends of the institute (Fig. 2). The highlight of this celebration was the farewell to Emeritus Professor Karl Peter Pfeiffer, who headed the institute from 1994 to 2009.


Fig. 2: Team

The Institute of Medical Statistics and Informatics provides a major contribution to the teaching of medical students. As well as offering compulsory lectures in semesters 1, 5 and 8, we focus on teaching diploma and PhD students. Students who are working on their diploma and PhD theses are advised on the use of appropriate statistical and epidemiological methods. Our new, weekly first aid lectures are highly appreciated by students looking for assistance with regard to research methodology.

Additionally, we provide statistical consultations to all researchers at MUI, with a focus on clinical studies. Statistical consulting and collaboration are fundamental to the strong publication record of the institute. In relation to the number of employees, the division has held a top ranking within MUI in recent years with respect to the total number of publications: between 2017 and 2020, a total of 173 original research papers were published by researchers from the institute as the first, senior or co-author.

Research

Cancer Epidemiology
Hanno Ulmer

In cancer epidemiology, we investigate metabolic and lifestyle factors as potential risk factors for cancer incidence and mortality. Metabolic syndrome is a cluster of factors characterised by obesity, hypertension, dyslipidaemia and high blood glucose. The prevalence of metabolic syndrome is rising worldwide. Individuals with metabolic syndrome have a higher risk of cardiovascular disease and diabetes, but less is known about the links with cancer.

We are participating in the Me-Can project, which holds a large database of health examination data of about 570,000 individuals from Sweden, Norway and Austria. Measurements such as height, weight, blood pressure, blood glucose, triglycerides and total cholesterol were recorded between 1972 and 2004. Individuals in the database have been followed until their death, emigration or the end of follow-up, according to the principles of epidemiological cohort studies. To obtain cause-of-death and cancer incidence information, the database has been linked to cancer registries in each country. The institute is a key player in the Me-Can project.

One important finding from the Me-Can project, which was recently published by Josef Fritz and Hanno Ulmer, is that insulin resistance is responsible for an increased risk of gastrointestinal cancers in obese individuals by comparison with individuals of normal weight, but there is no such link in the case of gynaecological cancers (Fig. 3). Michael Edlinger investigated links between pre-diagnostic blood glucose levels, diabetes and glioma, and found an inverse correlation between blood glucose and risk of glioma.


Fig. 3: Effects of TyG index and BMI (total effect (in green) as well as indirect effect from TyG index (in red)) on cancer risk, classified by cancer site. All models have been adjusted for baseline age, sex, smoking status, fasting status, cohort and decade of birth.

In cancer epidemiology, we have also successfully completed a case-control study, investigating the connection between aluminium exposure and breast cancer. This study was conducted in close cooperation with MUI scientists from the departments of Gynaecology, Plastic Surgery and Biochemistry.

Michael Edlinger (treasurer) and Hanno Ulmer (founding president) established the Austrian Society of Epidemiology. The society gained over 100 members during its first five years and has been scientifically involved with a wide range of activities, including a recent online symposium entitled “Covid19, a stress-test for epidemiology”. An international jury selected Josef Fritz from our institute as the 2020 winner of the society’s annual “best paper” award.

Josef Fritz was awarded a US scholarship to the Max Kade Foundation by the Austrian Academy of Sciences, and Katie Bates recently received a Lise Meitner scholarship from FWF.

Cardiovascular Epidemiology
Hanno Ulmer, Michael Edlinger

Using data from the population-based Vorarlberg health examination database (VHM&PP), we have been investigating the role of metabolic risk factors such as obesity, blood pressure, blood lipids, blood sugar, gamma-glutamyltransferase and uric acid in cardiovascular disease since 2003. The latest publication in a long tradition focused on the validation of prediction models for cardiovascular disease in the elderly (Fig. 4).


Fig. 4: Predicted versus observed cardiovascular death within 10 years, by age (65 – 80 years) and sex (%). Predicted mortality was calculated using the SCORE O.P. risk function for low-risk regions and validated in the study population of the VHM&PP.

The VHM&PP database further enables Hanno Ulmer to collaborate with the NCD Risk Factor Collaboration (NCD-RisC) group. In recent years, NCD-RisC has published prevalence studies internationally on body weight and height (children and adults), hypertension, diabetes and hypercholesterolaemia. A recent publication in Nature showed that: “rising rural body-mass index is the main driver of the global obesity epidemic in adults.”

Michael Edlinger has validated and developed ordinal prediction models for the diagnosis of non-obstructive coronary artery (and multi-vessel) disease, using data from the CARDIIGAN cohort. Based on this and other research, Michael Edlinger completed his habilitation in 2019.

Josef Fritz has applied state-of-the-art statistical mediation analysis techniques to data from the Malmö Diet and Cancer Study, to analyse the role of cardiovascular risk factors as mediating factors in respect of genetic risk of cardiovascular disease.

In collaboration with the department of cardiac surgery, we have been able to show that a positive family history has beneficial effects on long-term outcome in young coronary artery bypass grafting patients. We explained this paradoxical finding with the aid of causal reasoning techniques and even attracted the interest of Judea Pearl, one of the grand masters in the field of causal inference (Fig. 5).



Fig. 5: Causal diagram representing the underlying connections between positive family history of premature cardiovascular disease and survival outcome. “Requiring CABG at young age” qualifies as a collider and explains the paradoxical finding of a beneficial effect of positive family history on survival after coronary artery bypass grafting.

Katie Bates has collaborated on the International Project on Cardiovascular Disease in Russia, aiming to understand the disproportionately high morbidity and mortality burden that Russia faces with respect to cardiovascular disease. The PIs are Professor David Leon (London School of Hygiene and Tropical Medicine) and Professor Martin McKee (London School of Hygiene and Tropical Medicine). To date, this collaboration has led to two publications: in BMJ Open Heart concerning the management of patients with ST segment elevation myocardial infarctions in Russia, and in BMC Cardiovascular Disorders comparing the pharmacological management of modifiable cardiovascular risk factors.

Clinical Trials and Registries
Hanno Ulmer

Multicentre trials with major participation from our institute include the EU-funded Gannet53 randomised control trials as well as other studies, such as the MiFlaPRO, NCT-CoV, DACH, STRETCH, ERCC1, ECMO and Nabilone trials. Marina Riedmann and Hanno Ulmer are trial statisticians in the international, multicentre phase-I and phase-II Gannet53 ovarian cancer treatment studies. Lucie Dostal and Sarah Maier provide high-quality statistical consulting to clinical researchers and actively participate in study planning and data analysis.

As the responsible IT manager, Lalit Kaltenbach has developed an e-CRF system for both multicentre trials as well as disease related registries including for the follow-up of Sars-Cov-2 patients. The institute runs five Austria-wide registries: the HIR registry, the PCI registry, the IIK registry, the ablation registry, and the Parkinson’s registry.

We support clinical researchers in all aspects of statistical study planning, protocol writing, applications for ethical review, data management, statistical analyses and publication. We provide expertise on the use of statistical (R, SAS, Stata, SPSS etc.) and data management software (REDCap).

To support researchers with submitting PhD and habilitation theses, Joachim Masser developed the PubMon programme. This facilitates administration of the personal publication record of MUI researchers, including impact factors, citations and journal rankings.

Statistical and Epidemiological Methods
Hanno Ulmer, Josef Fritz

Although the division has had a strong research record in classification and regression methods over the years, we are now setting a new focus in the field of causal inference, developing and applying mediation analysis techniques to epidemiological research problems. Taking into account potential outcomes, so called counterfactuals, these techniques aim to detect the underlying mechanisms and to clarify why and how exposure produces the outcome of interest. Josef Fritz and Hanno Ulmer are currently working on statistical methods that allow multiple mediators in complex situations and they are applying these methods to a study, with the aim of better understanding of the underlying mechanism of the effect of obesity on risk of end-stage chronic kidney disease.

Biobanking and BioMolecular Resources Research Infrastructure (www.BBMRI.at)
Georg Göbel

BBMRI.at, an Austrian project, aims to develop a cutting-edge biobanking infrastructure for Austria, in order to increase cooperation and harmonisation among biobanks and towards industry. Since 2014, the local research team has worked on establishing common guidelines for the collection of human biosamples and on data management, in order to implement a university-wide, state-of-the-art biobanking infrastructure at the Medical University of Innsbruck. The project is being conducted in close cooperation with Tirol Kliniken local hospital management. Reference processes based on the CEN technical specification for molecular in vitro diagnostic examinations are currently in development by an inter-institutional working group. Their aim is to specify pre-examination processes for various material types, such as snap-frozen or FFPE tissue, venous whole blood, serum, plasma and urine.

At present, several independent, decentralised collections of human biomaterials are located in different MUI divisions. Based on the approval of the local ethics committee, most of these separate sample collections are linked to pseudonymised, detailed clinical data. The project aims to integrate archived biospecimens with clinical and molecular data, in a collaborative environment that emphasises scientific insights whilst ensuring security and compliance. An upcoming issue will be the digitalisation of FFPE slides. In addition, a comprehensive biobank management system will be launched, in order to support researchers with collection, sample and quality management tasks. The software will enable users to integrate patient materials, clinical, specimen, genetic and molecular assay data, in order to deliver a holistic, unified view; it facilitates data exploration and hypothesis-driven research without extra programming or IT support. Multi-level user access controls ensure that all collaborators can work effectively, whilst ensuring compliance with patient consent and maintaining regulatory guidelines.

Medical Informatics, Artificial Intelligence and Deep Learning
Georg Göbel, Maryam Sadeghi

In the context of experimental brain images, the registration of histological images to an atlas is still challenging in terms of accuracy, universality and time efficiency. The first issue is that brain histological datasets often suffer from artefacts, such as enlarged ventricles (holes), missing tissue, folding, air bubbles, uneven staining, tears or slice-independent distortions. Second, due to brain tissue elasticity, the sections are easily deformed during slice preparation procedures. Consequently, when computing this warp field, the elasticity of different regions in the brain and its mechanical properties must be taken into account. Third, because of the warped nature of the histological brain images, there is no ground truth data for the boundaries of the anatomical regions.

Maryam Sadeghi is currently investigating deep learning methods to register histological mouse brain slices, using a standardised annotated mouse brain atlas. Her software provides a deep learning-based registration method, which can be evaluated by means of a validation measure in comparison with ground truth data. Additionally, it can be used to explore ways to simulate ground truth data, which can be used to validate the registration methods of the software.

Florian Merkle is currently applying an array of state-of-the-art attack methods from the general field of computer vision, evaluating the robustness of medical imaging deep learning architectures against these types of attack. His project will create awareness of and sensitivity to the flaws of current deep learning systems and their specific implications in the medical sector.

Selected Publications

  • Fritz, Josef; Bjørge, Tone; Nagel, Gabriele; Manjer, Jonas; Engeland, Anders; Häggström, Christl; Concin, Hans; Teleka, Stanley; Tretli, Steinar; Gylling, Björn; Lang, Alois; Stattin, Pär; Stocks, Tanja; Ulmer, Hanno: The triglyceride-glucose index as a measure of insulin resistance and risk of obesity-related cancers. INT J EPIDEMIOL. 2020 Feb 1;49(1):193-204.
  • Ruttmann, Elfriede; Abfalterer, Hannes; Dietl, Marion; Wagner, Julian; Kilo, Juliane; Grimm, Michael; Bates, Katie; Fritz, Josef; Ulmer, Hanno: Positive family history of cardiovascular disease and long-term outcomes after coronary artery bypass grafting: a genetic paradox? EUR J CARDIOTHORAC SURG. 2020 May 1;57(5):986-993.
  • Mühlberger, Volker; Kaltenbach, Lalit; Bates, Katie; Ulmer, Hanno: Austrian National Cardiac Catheterization Laboratory Registry (ANCALAR), Österreichische Kardiologische Gesellschaft (ÖKG). Cardiac catherization in Austria: Results from the Austrian National Cardiac Catheterization Laboratory Registry (ANCALAR) 2012-2018. WIEN KLIN WOCHENSCHR. 2020 Feb;132(3-4):79-89.
  • Edlinger, Michael; Doerler, Jakob; Ulmer, Hanno; Wanitschek, Maria; Steyerberg, Ewout W.; Alber, Hannes F.; Van Calster, Ben: An ordinal prediction model of the diagnosis of non-obstructive coronary artery and multi-vessel disease in the CARDIIGAN cohort. INTERNATIONAL JOURNAL OF CARDIOLOGY. 2018; 267(S); 8-12.
  • Edlinger, Michael; Wanitschek, Maria; Doerler, Jakob; Ulmer, Hanno; Alber, Hannes F.; Steyerberg, Ewout W.: External validation and extension of a diagnostic model for obstructive coronary artery disease: a cross-sectional predictive evaluation in 4888 patients of the Austrian Coronary Artery disease Risk Determination In Innsbruck by diaGnostic ANgiography (CARDIIGAN) cohort. BMJ OPEN. 2017; 7(4); e014467.
  • Schwartzbaum, Judith; Edlinger, Michael; Zigmont, Victoria; Stattin, Par; Rempala, Grzegorz A.; Nagel, Gabriele; Hammar, Niklas; Ulmer, Hanno; Foeger, Bernhard; Walldius, Goran; Manjer, Jonas; Malmstrom, Hakan; Feychting, Maria: Associations between prediagnostic blood glucose levels, diabetes, and glioma. SCIENTIFIC REPORTS. 2017; 7(S); 1436.
  • Fritz, Josef; Shiffman, Dov; Melander, Olle; Tada, Hayato; Ulmer, Hanno: Metabolic Mediators of the Effects of Family History and Genetic Risk Score on Coronary Heart Disease-Findings from the Malmö Diet and Cancer Study. JOURNAL OF THE AMERICAN HEART ASSOCIATION. 2017; 6(3); e005254.
  • Linhart, Caroline; Talasz, Heribert; Morandi, Evi M.; Exley, Christopher; Lindner, Herbert H.; Taucher, Susanne; Egle, Daniel; Hubalek, Michael; Concin, Nicole; Ulmer, Hanno: Use of Underarm Cosmetic Products in Relation to Risk of Breast Cancer: A Case-Control Study. EBIOMEDICINE. 2017; 21(S); 79-85.
  • Hofer-Picout, Philipp; Pichler, Horst; Eder, Johann; Neururer, Sabrina B.; Mueller, Heimo; Reihs, Robert; Holub, Petr; Insam, Thomas; Goebel, Georg: Conception and Implementation of an Austrian Biobank Directory Integration Framework. BIOPRESERVATION AND BIOBANKING. 2017; 15(4); 332-340.

Selection of Funding

  • US Fellowship of the Max Kade Foundation (Josef Fritz), Mediation Analysis in Circadian Epidemiology (2019-2020)
  • Lise Meitner scholarship (Katie Bates) The Ischgl Follow-up study (FUPS Ischgl), FWF M3069-B

Collaborations

  • Tone Bjorge, Bergen University, Bergen, Norway
  • Ben Van Calster, KU Leuven, Leuven, Belgium
  • Hans Concin, Arbeitskreis für Vorsorge- und Sozialmedizin, Bregenz, Austria
  • Cecily Kelleher, University College Dublin, Dublin, Ireland
  • Gabriele Nagel, University of Ulm, Ulm, Germany
  • Martin McKee, London School of Hygiene and Tropical Medicine, London, UK
  • Ruth Pfeiffer, National Cancer Institute, Bethesda MD, USA
  • Par Stattin, Umea University, Umea, Sweden
  • Ewout Steyerberg, Erasmus MC University Medical Centre Rotterdam, Rotterdam, the Netherlands
  • Tanja Stocks, Lund University, Malmo, Sweden

ao. Univ.-Prof. Mag. Dr.rer.soc.oec. Hanno Ulmer
Director
Contact:
Schöpfstraße 41/1
6020 Innsbruck
Austria
Email: hanno.ulmer@i-med.ac.at
Phone: +43 512 9003 70900
www.i-med.ac.at/msig 

Research Report